Before the Thanksgiving holiday, I wrote a blog post about a study that described enhanced SARS-CoV-2 entry into cells that express the neuropilin-1 receptor (NRP1). The main takeaway from that piece was that while NRP1 is not sufficient for viral entry, it greatly enhances viral entry when coexpressed with ACE2 and TMPRSS2, the two proteins responsible for entry. The authors of the study had also found that NRP1 was highly expressed in cells isolated from the bronchoalveolar lavage fluid from COVID-19 patients relative to control patients. Overall, this study suggested that NRP1 expression in the olfactory mucosa likely plays an important role in mediating some of the neurological symptoms we have seen in COVID-19, such as anosmia and ageusia. An important missing link in viral-associated anosmia is whether the virus could enter sensory neurons from infected epithelium, and subsequently spread to the brain from infected sensory neurons.
Earlier this week, a study published in Nature Neuroscience suggests that not only is the virus invading the olfactory mucosa, but it is also reaching olfactory neurons through the infected epithelium. Using immunohistochemistry, in situ hybridization, and electron microscopy, Meinhardt et al. found “SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain” from autopsy tissues of 33 individuals with COVID-19. They found high levels of SARS-CoV-2 RNA in the olfactory mucosa, as well as S protein within the cytoplasm of endothelial cells. The authors claim that the “presence of intact CoV particles together with SARS-CoV-2 RNA in the olfactory mucosa [and] in neuroanatomical areas receiving olfactory tract projections may suggest SARS-CoV-2 neuroinvasion occurring via axonal transport.” This point is important because there has been a lot of published opinion pieces debating whether or not this virus is capable of traveling via axons and this is the first piece of evidence that I have seen to suggest that it may be doing so. This has so far been difficult to prove (and is not yet totally proven) because detecting individual viral particles within axons is incredibly difficult due to the low number of viral particles and the lack of the viral reproduction machinery within axons (replication is expected to occur in the somata). Nonetheless, they also found that in some individuals, SARS-CoV-2 RNA was detected within the cerebellum, which does not have a direct connection to the olfactory mucosa, suggesting that other mechanisms of viral entry into the CNS may also be occurring. This important study brings us a step closer to understanding the complex question of how SARS-Co-V-2 mediates neurologic injury.
References
Meinhardt, J., Radke, J., Dittmayer, C. et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci (2020).
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